As opposed to other tissues, the kidney exhibits abundant constitutive expression of inducible cyclooxygenase-2 (COX2) (18). Within the kidney, the vast majority of COX2 resides in the stromal/interstitial cells, with some COX2 expressed in the cortex in epithelial cells on macula densa and its adjacent fragment of cortical thick ascending limb. Studies indicate cyclooxygenase inhibiting non-steroidal anti-inflammatory drugs (NSAIDs), including newly developed COX2 selective inhibitors (celecoxib, rofecoxib), cause sodium retention and hypertension in certain subsets of patients (21, 63, 64), pointing to an important role of renal COX2 mediated prostaglandins in regulating salt absorption and systemic blood pressure. Animal studies show renal medullary COX2 is markedly induced by high salt diet (69), consistent with the role of renal medullary COX2 in maintaining body sodium homeostasis. The present proposal will examine the hypothesis that high salt induced renal medullary interstitial (stromal) COX2 plays an important role in regulating renal medullary blood flow, salt excretion and maintaining systemic blood pressure. Defining the role of COX2 in renal interstitial cells should provide valuable information in identifying target molecule(s) or receptor(s) of renal COX2 mediated PGs. The proposed studies will have three specific aims: Specific Aim I: To examine the mechanism underlying high salt diet induced COX2 expression. Specific Aim II: To examine the role of renal medullary interstitial cell COX2 in modulating sodium excretion and maintaining blood pressure following high salt loading. Specific Aim III: To define the down-stream target of activated renal medullary COX2 expression.